Formaldehyde is an important industrial chemical to which millions of workers are exposed worldwide. Environmental exposures can also be significant as a result of off-gassing in new mobile homes and from combustion. The International Agency of Research on Cancer (IARC) recently classified formaldehyde as a human carcinogen that causes nasopharyngeal cancer and also concluded that there is "strong but not sufficient evidence for a causal association between leukemia and occupational exposure to formaldehyde". Although several epidemiological studies and our new meta-analysis support an association with leukemia, some investigators have argued that inhaled formaldehyde cannot reach the bone marrow, is not toxic to the hematopoietic system, and thus cannot cause leukemia. In order to improve our understanding of the biological plausibility of formaldehyde-induced leukemogenesis, we have developed a number of working hypotheses that we will test in five Specific Aims proposed as part of two biomarker population studies of formaldehyde- exposed workers in China (Formaldehyde Biomarker 1 and 2: FAB1 &FAB2). We plan to develop valid biomarkers of formaldehyde exposure and early biological effect in FAB1;to determine if formaldehyde toxicity can be reproduced in vitro;and, to confirm its hematotoxicity and genotoxicity, and examine dose-response relationships in a larger biomarker study of 1,000 workers (FAB2). To achieve these goals, we will first employ the OctoChrome FISH technique, developed and validated in studies of the well-known leukemogen, benzene, to determine for the first time if a direct link exists between human formaldehyde exposure and leukemia- specific chromosomal aberrations in peripheral blood lymphocytes (Aim 1) and circulating myeloid progenitor cells (Aim 2). We will then measure DNA-protein crosslinks as a biomarker of internal dose and genotoxic damage from formaldehyde in the exposed individuals and correlate the findings with chromosome alterations (Aim 3). Human cell culture studies in vitro will be performed in an attempt to validate our findings from the population studies, to determine if the chromosome changes and DNA damage observed in exposed workers can be attributed to formaldehyde (Aim 4). In collaboration with investigators at U.S. NCI, China GDPCC and Utrecht University, we will conduct a larger biomarker population study (FAB2) with a wide range of exposure to confirm the hematotoxicity and genotoxicity of formaldehyde and to examine dose-response relationships (Aim 5). Specifically, in the FAB2 study, we will determine complete blood cell counts in a population of 500 exposed workers and 500 unexposed frequency-matched controls in China with well-characterized exposures to formaldehyde;and, we will culture progenitor cells from 100 highly exposed and 100 control subjects, so that colony formation and leukemia-specific chromosome alterations can be measured. These findings are anticipated to provide important information on the potential mechanisms of formaldehyde-induced leukemia that will assist in the public health risk assessment and regulation of formaldehyde. PUBLIC HEALTH RELEVANCE: Formaldehyde is an important industrial chemical that may cause leukemia, but the absence of a plausible mechanism makes this topic highly controversial. We plan to perform two studies of formaldehyde-exposed workers in which we will examine DNA damage and chromosome changes associated with leukemia. The data produced from these studies will be useful to public health agencies in their evaluation of the leukemia risk presented by formaldehyde.